Investigating the clinical ontologies of loss-of-function and gain-of-function human gene variants

项目摘要/摘要 这项建议是针对医学博士/博士生的个人博士前奖学金申请。约瑟夫·帕克 申请者正在考虑中，提出了一项研究培训计划，其长期目标是发展成为一个 独立内科医生-科学家，研究心脏代谢和其他疾病的遗传机制 使用计算、实验和转换方法的复杂疾病。全基因组关联 研究已经成功地描述了常见的遗传变异在人类疾病中的作用 分析具有共同疾病特征的大量人群，但许多基因的临床本体论仍然存在 通过这些基于表型的方法不完全描述。此外，一个根本的问题是 基因关联研究仍然很难描述疾病的功能后果-- 与其各自基因产物相关的变异(即功能丧失与功能获得)。《宾夕法尼亚医学》 Biobank，一个基于医疗保健系统的基因、全外显子组测序和电子健康数据库 记录(EHR)数据，允许无偏见、基因优先的方法来描述 通过表型全基因组在临床环境中捕获的功能障碍基因和人类疾病特征 联合研究(Phewas)。通过基因负担Phewas测试，拟议的研究旨在表征 由基因组上每个基因罕见的功能丧失突变引起的疾病的临床表现- 规模很大。我们的分析将使临床医生能够更有效地在他们的 临床环境中的患者。此外，除了我们对功能丧失突变的审问外，我们的 拟议的项目有可能确定已知的功能获得突变在人类疾病中的作用 并识别与疾病相关的新的功能获得变体，为研究人员提供设计方向 基础科学的后续实验研究以及促进更有效治疗的平台 发现。重要的是，在进行拟议的研究时，约瑟夫将接受严格的培训 计算生物学和统计遗传学在资助期内，推动他成熟为 成功的、独立的内科科学家为临床职业生涯做好了充分的准备，包括分析 “组学”和“大数据”。这些目标将通过广泛的联谊培训计划共同实现。 由他和他的赞助商丹尼尔·雷德开发。在众多高级调查员的指导下， 定期参加研讨会、会议和其他介绍和互动的机会 宾夕法尼亚大学的著名科学家和协作研究环境 雷德实验室及其周边组织推动，约瑟夫已做好准备实现他的 通过他在拟议的培训期间得到保证的发展来实现职业目标。

PROJECT SUMMARY/ABSTRACT This proposal is for an MD/PhD student’s individual pre-doctoral fellowship application. Joseph Park, the applicant under consideration, proposes a research training plan with the long-term goal of developing into an independent physician-scientist studying the genetic mechanisms underlying cardiometabolic and other complex diseases using computational, experimental, and translational approaches. Genome-wide association studies (GWAS) have successfully described the roles of common genetic variation on human diseases by analyzing large populations with shared disease traits, but the clinical ontologies of numerous genes remain incompletely described through these phenotype-based methodologies. Additionally, a fundamental problem of genetic association studies remains to be the difficulty of describing the functional consequences of disease- associated variants to their respective gene products (i.e. loss- vs. gain-of-function). The Penn Medicine Biobank, a healthcare system-based database of genotype, whole-exome sequencing, and electronic health record (EHR) data, allows for an unbiased, genotype-first approach to describing the relationships between dysfunctional genes and human disease traits captured in the clinical setting through phenome-wide association studies (PheWAS). Through gene-burden PheWAS tests, the proposed study aims to characterize the clinical manifestations of disease caused by rare, loss-of-function mutations in each gene on a genome- wide scale. Our analyses will enable clinicians to more effectively identify genetic diseases among their patients in the clinical setting. Furthermore, in addition to our interrogation of loss-of-function mutations, our proposed project has the potential to define the roles of known gain-of-function mutations in human disease and identify novel gain-of-function variants relevant to disease, offering a direction for investigators to design follow-up experimental studies in the basic sciences as well as a platform promoting more efficient therapeutic discoveries. And importantly, while conducting the proposed study, Joseph will receive rigorous training in computational biology and statistical genetics during the funding period, promoting his maturation into a successful, independent physician-scientist thoroughly prepared for a clinical career involving the analysis of “omics” and “big data”. These goals will be accomplished through the extensive fellowship training plan jointly developed by him and his sponsor, Daniel Rader. Through the mentorship of numerous senior investigators, regular attendance at seminars, conferences, and other opportunities for presentation and interaction with renowned scientists at the University of Pennsylvania, and the collaborative research environment that the Rader laboratory and its physically surrounding organizations promote, Joseph is well-equipped to achieve his career goals through his guaranteed development during the proposed training.